Treatment of Diabetic Foot UlcersImmun., Endoc. & Metab. Agents in Med. Chem.,
, Vol. 7, No. 1
becomes infected. In each of these stages a specific inter-vention could help to prevent further progression. Examplesare shoe wear to reduce the elevated plantar pressures, chi-ropody in case of callus, immobilisation and/or local meas-ures to reduce biomechanical stress in case of an impedingulcer, specific off-loading devices such as the total contactcast in case of an ulcer and finally bed rest, antibiotics and, if necessary surgery in case of an infected ulcer. Although at-tractive, this scheme does not seem to fit all patients. Pro-spective studies have indeed shown that elevated peak plan-tar pressures during walking can predict future ulceration inpatients with diabetic neuropathy [7, 27], but the predictivevalue of elevated foot pressures is relative low (sensitivity64% and specificity 46%) . In an intriguing study of Armstrong
. using continuous activity monitoring inpatients with neuropathy, the subjects who developed aplantar ulcer had unexpectedly a lower overall daily activitythan the their non-ulcerated counterparts. . Althoughseveral biomechanical explanations are possible  thesestudies suggest perhaps in addition to elevated foot pres-sures, other factors could play a central role in plantar footulceration. Finally, preliminary data of a large Europeanstudy of the Eurodiale consortium suggest that only a relativesmall number of patients do have such a classical ulcer onthe plantar forefoot. The majority (>70%) of ulcers werelocated on other areas such as toes or the dorsum of the foot(L. Prompers, personal communication). In these patientsother factors must be responsible for ulceration, such as ele-vated shear forces due to ill-fitting shoes or impaired of mi-crocirculatory blood flow responses to relative low externalpressure . However, the impressive healing rates that canbe observed with off-loading techniques in (neuro-)ischemiculcers, as described below, are a strong argument that oncean ulcer has developed, increased biomechanical stress im-pedes healing.
PERIPHERAL VASCULAR DISEASE
Atherosclerotic, obstructive, peripheral arterial disease(PAD) is a major determinant of the outcome of a diabeticfoot ulcer . PAD is a common finding in patients withtype 2 diabetes mellitus, with a prevalence of approximately20 to 40% [32, 33]. In many patients the disease has no orfew symptoms and runs a relatively benign course, but inothers it leads to gangrene or impaired healing of foot ulcers.PAD in diabetes frequently has a specific anatomical pattern,which can be interpreted as a sign of premature ageing of thevascular tree. The proximal vessels are relatively spared,with less involvement of the aortic iliac arteries and moreextensive disease in the arteries of the lower leg [34-36]. Indiabetic patients, the atherosclerotic changes seem to bemore extensive and also more aggressive, with a faster pro-gression of disease. McDaniel showed that patients withclaudication and diabetes had a 35% risk of sudden ischemiaand a 21% risk of major amputation, compared to 19 and3%, respectively, in non-diabetic patients . Major riskfactors for the development of PAD (other than diabetes) areolder age, smoking, and possibly hypertension . Recently,several novel risk factors have been identified in the generalpopulation for the development of PAD, such as hyperhomo-cysteinemia, elevated markers of inflammation, and insulinresistance [38-42].
Evaluation of the adequacy of tissue perfusion in the feetof diabetic patients can be a difficult clinical challenge, asalmost all tests have a moderate accuracy in predicting out-come. Many patients do not have claudication or severeischemic rest pain, probably due to sensory neuropathy.However, if claudication or rest pain are present, the prob-ability of amputation is greatly enhanced . The pulses of the femoral, popliteal, dorsalis pedis, and posterior tibialartery should be palpated. The proximal vessels should beauscultated for bruits, particularly the iliofemoral segment. If both foot arteries are palpated, severe ischemia is unlikely.Additional signs of severe ischemia are skin necrosis, gan-grene, and blanching of the feet on elevation with a red-purple discoloration on dependency (in the absence of infec-tion). Other signs are probably of little value in diabetic pa-tients . The colour and temperature of the skin is usuallynot helpful as the feet of diabetic patients can be red andwarm, despite (severe) ischemia, which is probably causedby the relative high (thermoregulatory) shunt blood in dia-betic patients with peripheral ischemia .Non-invasive vascular evaluation is indicated in case of nonpalpable pulses, or other signs of ischemia and in non-healing ulcers. In nondiabetic patients measurement of thesystolic arterial pressure at the ankle with a hand held Dop-pler is a reliable screening test for severe ischemia .Also, in diabetic patients an absolute ankle pressure less than50 mmHg indicates critical limb ischemia. However, due tomedia calcification, these arteries can become less com-pressible in diabetic patients, resulting in falsely elevatedankle pressures. Ankle pressures above 50 mmHg, therefore,are of very limited predictive value. In contrast, measure-ment of systolic toe pressures is probably more reliable andcan predict wound healing in diabetic patients . In par-ticular, values below 30 mmHg are associated with a pooroutcome, and values between 30 and 50 mmHg should alertthe clinician of the possibility of severe PAD. Unfortunately,toe pressure measurements can also be affected by mediacalcification in a minority of patients. Measurement of thetranscutaneous pressure of oxygen (TcPO
) can give addi-tional information on the probability of wound healing .Wound healing is very unlikely if TcPO
values are below20-30 mmHg and healing is likely with a TcPO
value above40 mmHg .If clinical and noninvasive assessments suggest signifi-cant PAD with a low probability of wound healing, or if thepatient has persistent rest pain, revascularisation should beconsidered in all patients . In these patients further inves-tigations are necessary to localise arterial lesions, to gradetheir severity, and to assess the possibility of a revasculari-sation procedure . As stated in the International Consen-sus, in all cases the arterial tree of the lower extremity shouldbe visualised. It is crucial to visualise the entire tibial andfoot circulation, as the former is a common location of themost significant occlusive lesion and the latter is an impor-tant potential site for the anastomosis of a distal bypass. Inmost centers angiography will be performed, but this tech-nique might be replaced progressively by magnetic reso-nance angiography (MRA) .